Amide formation is a fundamental reaction in chemical synthesis (1). The importance of amides in chemistry and biology is well recognized and has been studied extensively over the past century (2-4). Although several methods are known for the synthesis of amides, preparation under neutral conditions and without generation of waste is a challenging goal (1, 5). Synthesis of amides is mostly based on activated acid derivatives (acid chlorides, anhydrides) or rearrangement reactions induced by acid or base which often involve toxic chemical waste and tedious work-up (5). Transition-metal catalyzed conversion of nitriles into amides was reported (6, 7, 8). Catalytic acylation of amines by aldehydes in the presence of a stoichiometric amount of oxidant and a base is known (9, 10). Recently, oxidative amide synthesis was achieved from terminal alkynes (11). Cu(I) catalyzed reaction of sulfonyl azides with terminal alkynes is a facile method for the synthesis of sulfonyl amides (12, 13).
Polyamides are one of the most important polymer classes, extensively used in fiber products, plastics and their derivatives, with many applications, including in biomedical studies. Recently, the synthesis of functional polyamides has received considerable attention. Generally, polyamides are synthesized by condensation of diamines and activated dicarboxylic acid derivatives and/or in the presence of coupling reagents. In some cases, ring opening of small-ring lactams at high temperatures leads to polyamides. To avoid the use of activators, waste generation, or harsh conditions, the development of economical, efficient and environmentally benign protocols are desirable.
The reverse reactions, i.e., reduction of amides and related carboxylic acid derivatives plays an important role in organic synthesis, both in laboratory and industrial processes. Traditionally, the reduction is performed using stochiometric amounts of hydride reagents, generating stochiometric amounts of waste (14). A much more attractive, atom-economical approach is a catalytic reaction using H2; however, hydrogenation of carboxylic acid derivatives under mild conditions is a very challenging task (15a-b), with amides presenting the one of the highest challenges among all classes of carbonyl compounds. A few examples of the important hydrogenation of amides to amines, in which the C—O bond is cleaved with the liberation of water (Scheme 1), were reported (16a-d). This reaction can also be affected with silanes as reducing agents (17a-b). In addition, the interesting hydrogenation of cyclic N-acylcarbamates and N-acylsulfonamides, which involves cleavage of the C—N bond, but does not form amines, was recently reported (18).
On the other hand, selective, direct hydrogenation of amides to form amines and alcohols has not been reported. Hydrogenation of amides to amines (via C—O cleavage, generating water) can have C—N cleavage as a side reaction, requiring the presence of water, and resulting from catalytic hydrolysis of the amides to acids and amines, followed by hydrogenation of the acids to alcohols (16 b-d) However, no amide C—N hydrogenolysis to form alcohols and amines was reported in the absence of water.
Amines and alcohols are used extensively in the chemical, pharmaceutical and agrichemical industries (19a-c). Design of such a reaction is conceptually challenging, since the first mechanistic step in amide hydrogenation is expected to be H2 addition to the carbonyl group to form a very unstable hemiaminal which, in the case of primary or secondary amides, spontaneously liberates water to form an imine; further hydrogenation of the imine then leads to amine formation (Scheme 1). For amine and alcohol formation, cleavage of the C—N bond in preference to the C—O bond is required.

The applicants of the present invention recently reported the dehydrogenation of alcohols catalyzed by PNP- and PNN-Ru(II) hydride complexes (20). Whereas secondary alcohols lead to ketones (21, 22), primary alcohols are efficiently converted into esters and dihydrogen (20-22). The dearomatized PNN pincer complex 1 (FIG. 1) is particularly efficient (23); it catalyzes this process in high yields under neutral conditions, in the absence of acceptors or promoters.
Given the widespread importance of amines, alcohols, amides, and related derivatives in biochemical and chemical systems, efficient syntheses that avoid the shortcomings of prior art processes are highly desirable.